Enterohemorrhagic Escherichia coli (EHEC) O157:H7 strains are major human food-borne pathogens, responsible for bloody diarrhea and hemolytic uremic syndrome (HUS). So far, there is no vaccine for humans against EHEC infections.
Enterohemorrhagic Escherichia coli (EHEC) strains are zoonotic extracellular pathogens, members of the Shiga-toxin producing E. coli (EHEC) pathogroup. EHEC causes sporadic outbreaks of diarrhea and hemorrhagic colitis, particularly in developed countries (reviewed in Nataro and Kaper, 1998, Clin Microbial Rev 11:142-201; Farfan and Torres, 2012, Infect lmmun 80:903-13; Nguyen and Sperandio, 2012, Front Cell Infect Microbial 2:90). In the United States, EHEC causes approximately 0.9 cases per 100,000 inhabitants, with a significant number of hospitalizations and death, particularly among children and the elderly (reviewed in Garcia-Angulo et al., 2013, Vaccine 31:3229-35; Marks et al., 2013, J Food Prot 76:945-52). E. coli O157:H7 comprises the serotype most commonly associated with outbreaks (Karmali et al., 2010, Vet Microbiol 140:360-70) and the expression of Shiga toxin (Stx), in addition to be linked to hemorrhagic colitis, it is associated with the progression to the hemolytic uremic syndrome (HUS), which cause renal failure and high fatality rate [reviewed in (Pacheco and Sperandio, 2012, Front Cell Infect Microbial 2:81)]. In addition, EHEC O157:H7 uses a type 3 secretion system (T3SS) to translocate effector proteins into the eukaryotic cell, causing changes in the host cytoskeleton, ultimately leading to improved bacterial adherence and colonization and, in some cases, host cell death (Wong et al., 2011, Mol Microbiol 80:1420-38). The EHEC T3SS is comprised of a basal ATP-dependent secretion apparatus, with an EscC polymer ring spanning bacterial outer membrane and a needle like structure formed by polymers of the EscF protein and an extension structure comprised of polymerized EspA. Finally, the EspD and EspB proteins form a translocon structure in the host membrane (Sekiya et al., 2001, Proc Natl Acad Sci USA 98:11638-43; Spreter et al., 2009, Nat Struct Mol Biol 16:468-76; Tree et al., 2009, Trends Microbial 17:361-70).
Generally asymptomatic, ruminants are the principal EHEC reservoir. Contaminated meat or fresh produce resulting from animal shedding constitutes an important route for human infection (Walle et al., 2012, Vet Immunol Immunopathol 152:109-20). Current prevention efforts are centered in the elimination of animal colonization, whether by vaccination or by improving sanitary and breeding practices (Walle et al., 2012, Vet Immunol Immunopathol 152:109-20; Varela et al., 2013, Zoonoses Public Health 60:253-68). Once the human infection is acquired, supportive care is provided, since antibiotic treatment could induce Shiga toxin expression. To date, two vaccines able to reduce EHEC colonization in cattle are commercially available (Varela et al., 2013, Zoonoses Public Health 60:253-68; Snedeker et al., 2012, Zoonoses Public Health 59:126-38). Nevertheless, development of other subunit-based vaccines has been focused in the T3SS and its associated proteins, as well as Stx (Garcia-Angulo et al., 2013, Vaccine 31:3229-35; Walle et al., 2012, Vet Immunol Immunopathol 152:109-20). For example, inactivated Stx-derivatives are able to induce Stx-neutralizing antibodies in mice (Ishikawa et al., 2003, Infect Immun 71:3235-39; Marcato et al., 2001, J Infect Dis 183:435-43) and hybrid A-B subunit-derived Stx toxins also induce antibody production and increase survival against toxemia and EHEC challenge in vivo (Cai et al., 2011, Vaccine 29:946-52; Bentancor et al., 2009, Clin Vaccine Immunol 16:712-18; Rojas et al., 2010, Clin Vaccine Immunol 17:529-36). Fusion proteins comprising of Stx-derived peptides and T3SS-related proteins are promising vaccine candidates. St2B-Tir-Stx1 B-Zot, Stx2B-Stx1 B-lnt281, EspA-Stx2A 1, EspA-IntiminC300-Stx2B and Stx2B-BLS fusions have been demonstrated to reduce EHEC colonization in animal models, such as mice and goats (Cheng et al., 2009, J Microbial 47:498-505; Gu et al., 2009, Microbes Infect 11:835-41; Gu et al., 2011, Vaccine 29:7395-03; Zhang et al., 2011, Vaccine 29:3923-39; Zhang et al., 2012, Vet Rec 170:178; Gao et al., 2009, Vaccine 27:2070-76; Gao et al., 2011, Vaccine 29:6656-63; Mejias et al., 2013, J Immunol 191:2403-11). Overall, cumulative information indicates that mucosal delivery routes seem to be an effective way to induce immune responses to block the adhesion of EHEC in the intestine, mainly through expression of secretory lgA (slgA) (Garcia-Angulo et al., 2013, Vaccine 31:3229-35).
In addition to the worldwide outbreaks caused by EHEC O157:H7, this organism has come recently under renewed scientific investigation as a result of the emergence of a subpopulation of strains that have acquired critical virulence factors that contribute to more severe and lethal disease in humans (Abu-Aii et al., 2010, PLoS One 5:e10167; Neupane et al., 2011, Microb Pathog 51:466-70). Further, the discovery of cattle reservoirs shedding high levels of EHEC O157:H7, which has been associated with the transmission between animals and across the human-animal interface (Arthur et al., 2013, Appl Environ Microbial 79:4294-4303; Matthews et al., 2009, Epidemics 1:221-29), strongly supports the idea that adoption of vaccination for livestock and/or susceptible individuals will have significant public health benefits, preventing substantial numbers of human EHEC O157 cases (Matthews et al., 2013, Proc Natl Acad Sci USA 110:16265-70). Therefore, further discovery for EHEC-specific antigens needs to be done to improve existing or to develop novel vaccines.